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  • FDA Grants Marketing Authorization to BioFire’s Multiplexed COVID Test – Lines Have Been Drawn

    On March 17, 2021, FDA granted BioFire Diagnostics’ De Novo, making it the first COVID assay originally authorized on a temporary basis for this public health emergency to be given permanent access to the US market. While FDA has only released the signed letter affirming their permanent marketing status, we can infer a few key points:

    1. This De Novo was product of collaboration between FDA and industry over the course of months.

    In the letter granting the De Novo it is important to note the date that the De Novo was “Received” by FDA May 19, 2020. This is significant as it means that it is very likely that the candidate device changed from the initial submission to the De Novo being granted. The BioFire® COVID-19 Test was initially authorized by FDA on March 23, 2020 which is well in advance of the DEN200031 being received by FDA.

    The BioFire Respiratory Panel 2.1 was submitted for FDA review under EUA202392 meaning that this EUA was originally submitted for FDA review sometime between mid-July and mid-September.  As this device was going to ‘set the bar’ for future clearances FDA likely allowed BioFire to add data and indications to the device from the original submission in March through at least October 2, 2020 when the BioFire Respiratory Panel 2.1 was originally authorized as an EUA assay.  It is reasonable to assume that if BioFire did not have enough data till mid/late summer to submit an EUA for the BioFire Respiratory Panel 2.1, they did not have enough data for a complete submission back in May 2020.

    While this is not typically allowed under normal circumstances it can be viewed as an action to everyone’s benefit as is explained below.

    2.  A more comprehensive De Novo submission allows for more EUA devices to declare this test as a predicate. The new regulation (21 CFR 866.3981) is as follows:

    Device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test.  A device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test is an in vitro diagnostic device intended for the detection and identification of SARS-CoV-2 and other microbial agents when in a multi-target test in human clinical respiratory specimens from patients suspected of respiratory infection who are at risk for exposure or who may have been exposed to these agents. The device is intended to aid in the diagnosis of respiratory infection in conjunction with other clinical, epidemiologic, and laboratory data or other risk factors.

    As shown by the bolded language, this regulation means that not only can the multitudes of single analyte RT-PCR tests claim this device as a predicate, but also the multiplexed assays will be able to use this De Novo as a predicate and proceed down a less burdensome 510(k) pathway.  Furthermore, the regulation is worded to encompass the expected mutation of the virus by defining the measurand as simply “nucleic acid targets” from “microbial agents that cause the SARS-CoV-2 respiratory infection.”

    Throughout the pandemic FDA has been very particular about the specific respiratory specimens a device has validated for use.  FDA had previous stratified the clinical matrices between the “upper” and “lower” respiratory tracts requiring, in most cases, a representative sample from each.  While the BioFire assay is only indicated for nasopharyngeal swabs, the regulation is crafted broadly to encompass samples from all portions of the respiratory tracts.

    It appears that this new regulation is only applicable to assays where the measurand is a nucleic acid.  This means that both antigen and antibody tests will likely need their own regulations created via the granting of De Novos for their respective technologies.

    3.  The controversial ‘FDA Reference Panel’ will likely survive the pandemic and fight on to plague industry for years to come. Item 5 of the Special Controls list states the following:

    When applicable, performance results of the analytical study testing the FDA recommended reference panel described in paragraph (b)(4)(vi) of this section must be included in the device’s labeling under 21 CFR 809.10(b).

    The reference panel was FDA’s attempt in the early stages of the pandemic to gain an understanding of assay performance across IVD manufacturers via a single standardized panel.  The panel was met with controversy as some test manufacturers were obtaining inconsistent or otherwise confounding results when using the test samples.  It appeared to many that the issue was not the tests but the panel.  Apparently, there are tests with perfectly good performance that, for some reason or other, are not optimized for the panel.

    This use of this panel began showing up in “Conditions of Authorization” for PCR EUAs making the testing compulsory when directed by FDA if a manufacturer wished to stay on the market.  In another surprise move, FDA used the performance on their reference panel to rank assays by sensitivity on a public facing website.  This website has not been maintained in recent months and is only current as of December 7, 2020.

    A manufacturer’s performance with this panel could yield both regulatory and business advantages.  If an assay performed well, it afforded the manufacturer the opportunity to pursue an asymptomatic claim for the assay before completing the required clinical study. The device would be considered a ‘more sensitive’ test that would potentially drive new business as a comparator for other assays.  Links to the website containing the data from FDA’s reference panel can be found in many of the issued EUA templates:

    From FDA’s “Molecular Diagnostic Template for Commercial Manufacturers” regarding “adding population screening of individuals without symptoms or other reasons to suspect COVID-19 to an authorized test”:

    If your assay is highly sensitive as determined by testing with the FDA SARS-CoV-2 Reference Panel or a recognized international standard, a post-authorization study may be appropriate.

    From FDA’s “Antigen Template for Test Developers” regarding “POC Clinical Evaluation”:

    The comparator method should be one of the more sensitive RT-PCR assays authorized by FDA. We encourage you to review the results from the FDA SARS-CoV-2 Reference Panel available here.

    Many manufacturers will likely hope that when FDA states “when applicable” in the special controls with respect to the reference panel that FDA means sometime after the eventual heat death of the universe.

    4.  This submission set the bar for all the other manufacturers wishing to stay on the market post-pandemic.

    A key parameter of substantial equivalence is the performance in the clinical agreement study. While OHT-7 typically posts the decision summary for public consumption it has yet to do so for this De Novo (we expect it to be posted in the coming days).  While the performance in the decision summary will be the true bar for substantial equivalence, we can look to the labeling for the EUA authorized device to get a preview of what to expect. On page 24 of the labeling, you can find the overall Sensitivity of this device for SARS-CoV-2 is 98% with a Specificity of 100%.  We do not know what this performance means for assays that had acceptable clinical agreement as an EUA authorized test (Sensitivity ≥95% and Specificity ≥98%) but do not meet this new bar for performance. As more COVID assay manufacturers scramble to convert their temporary marketing authorization afforded by the EUA pathway into a permanent clearance, these initial devices will be compared to BioFire’s to determine substantial equivalence.  If FDA clears a device with a lower sensitivity and specificity than BioFire’s this new device can then be used a predicate for others thereby lowering the bar for substantial equivalence for the rest of industry.

    This incremental lowering of acceptable performance standards is a permanent fixture in FDA’s thinking when it comes to clearing device via the 510(k) pathway. Typically, OHT-7 is more intractable than Captain Picard when facing the Borg when it comes to clearing a test with lower clinical performance than the declared predicate. We do not yet know how FDA will apply the substantial equivalence paradigm in the future but granting a De Novo to a device with very high clinical agreement could be used as a gating mechanism to weed out devices that were adequate for the pandemic, but not suitable as a permanent fixture in the US market.

    FDA Introduces Biocompatibility Assessment Resource Center

    Over the past several years, FDA has faced criticism stemming from high-profile device issues related to materials, including the Essure permanently implanted birth control device and metal-on-metal hip implants. Given this, it is not surprising that device biocompatibility has received greater focus in FDA premarket reviews for medical devices.  FDA  initially issued Use of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process” (Guidance) in 2016 to provide guidance to sponsors of premarket applications on evaluation of biological risk and biocompatibility testing for devices that are in direct or indirect contact with the human body.  However, many device sponsors have continued to face challenges demonstrating device biocompatibility, with many sponsors receiving additional information requests related to the biocompatibility data necessary to support a marketing application.  The Guidance describes a risk-based approach where justification may be provided to support the overall testing strategy and interpretation of results.  Many additional information requests that we have seen relate to disagreements between FDA and the sponsor with respect to justifications provided by the sponsor on what tests are applicable to the device, how the device tested is representative of the device intended for commercialization, the impact of differences between device tested and the device intended for commercialization, test methods, especially for extraction, and interpretation of results.

    On March 19, 2021, FDA announced the launch of an online Biocompatibility Assessment Resource Center to provide more clarity for sponsors navigating biocompatibility requirements.  The new resource is intended to explain terms and concepts for use in conjunction with the Guidance.  The site is divided into four steps:  1) Biocompatibility Basics, 2) Evaluation Endpoints, 3) Test Articles, and 4) Test reports.

    Biocompatibility Basics provides a very high-level description of the basis for biocompatibility and a glossary of biocompatibility terms.  In some ways, it is a repackaging of the Guidance.  The Basics page describes devices for which biocompatibility information is needed, what FDA assesses or evaluates, how FDA assesses or evaluates biocompatibility and biocompatibility factors of interest to FDA.  In the glossary, there is quite a bit of overlap in terms defined compared to the Guidance, with some new terms added, most of which come from the ISO 10993 series of biocompatibility standards.

    Evaluation Endpoints provides the same information as Attachment A of the Guidance in an easy-to-use format.  One statement of note is that FDA indicates that device categorization information can be obtained informally via e-mail or as part of the pre-submission process.  Information on Test Articles includes the same information as Attachment F of the guidance, providing example text to use when relying on biocompatibility data from a test article that is not the final, finished device, e.g., when using an identical material to that used in another cleared device.  Information on Test Reports includes the same information as Attachment E of the Guidance.

    While these resources may prove helpful to those new to biocompatibility, for those familiar with the Guidance, there is not likely much value other than the convenient format and it is not likely to help resolve the biocompatibility challenges faced by sponsors during premarket review.  It is nice to see informal e-mail mentioned as a way to get questions answered, but use of the Guidance and the pre-submission process will continue to be the best way to determine testing necessary to support a device’s biocompatibility before conducting studies.

    Categories: Medical Devices

    Pitfalls of the Notification Pathway – “I’m Sciencing as Fast as I Can”

    On August 25th, 2020 Hyman, Phelps & McNamara, P.C. released a blog post covering experiences and lessons learned from our interactions with FDA and what was at the time the new and unfamiliar EUA pathway (FDA, Testing, and COVID-19: A “Mid-Mortem”). In the six months since that post, we have seen new products hit the market for non-laboratory use, new technologies, and what I assume is attributable in some small part to my offerings to Jupiter, Son of Saturn, an effective vaccine.

    Since the early days of the pandemic, FDA has made it possible for manufacturers to market and distribute certain diagnostic tests to high-complexity CLIA Labs prior to EUA authorization provided that the validation testing is complete at the time of marketing and an EUA is filed with 15 business days. The “Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised) Immediately in Effect Guidance for Clinical Laboratories, Commercial Manufacturers, and Food and Drug Administration Staff” Issued on May 11, 2020 (the “FDA Testing Policy”).

    FDA does not intend to object to a commercial manufacturer’s development and distribution of SARS-CoV-2 test kits for specimen testing for a reasonable period of time, where the test has been validated and while the manufacturer is preparing its EUA request, where the manufacturer gives notification of validation to FDA as described below, and where the manufacturer provides instructions for use of the test and posts data about the test’s performance characteristics on the manufacturer’s website.

    On the surface, this statement sounds fantastic.  FDA appeared to understand that the pandemic is an all-hands-on-deck situation and is trying to find a middle ground to get tests on the market while manufacturers play catch-up compiling their EUA submission. But, in the words of the many great home shopping spokespeople, “But Wait! There’s More!”  The FDA Testing Policy states:

    FDA believes that 15 business days is a reasonable period of time to prepare an EUA submission for a test that has already been validated. Soon after receiving the EUA request, FDA will perform a preliminary review to identify if there are any problems with the performance data. If a problem is identified, FDA intends to work with the manufacturer to address the problem (e.g., through labeling or bench testing). If the problem is significant and cannot be addressed in a timely manner, and the manufacturer has already distributed the device, FDA would expect the manufacturer to suspend distribution and conduct a recall of the test.

    Per this policy, FDA is affording companies at least 3 weeks to compile completed data into a functional EUA submission and submit while also committing to a triage review with a tiered approach to deficiencies.  Hundreds of companies took advantage of this program and notified FDA of their intent to distribute test kits in accordance with FDA’s policy. This seemed too good to be true, and it most certainly was.

    Many companies viewed the notification pathway as a way to stand out from the crowd by proactively signaling to FDA that their submission was complete and that their EUA should garner additional attention from the Agency. For many companies the notification pathway was only about visibility on FDA’s radar. In our experience, many manufacturers never availed themselves of the opportunity to distribute as nearly all potential customers were seeking out tests that had successfully obtained EUA authorization.

    Weeks in the EUA queue turned into months with little to no action being taken by FDA for many EUAs on the notification list.  When companies finally received the reviewer introduction email, many were lifted from the morass of uncertainty and despair and filled with new hope for the future.  This life-reaffirming high would be snuffed out quickly by the all too common subsequent “Inadequate Validation” email.

    This email would inform companies that they had not provided complete information to demonstrate that the studies performed are adequate to validate the test and support the claimed performance characteristics of the device.  The email would go on to list the deficiencies in the familiar fashion of a hold letter for a 510(K), De Novo, or PMA.  As you’ll recall, the FDA Testing Policy stated that, “If a problem is identified, FDA intends to work with the manufacturer to address the problem (e.g., through labeling or bench testing).” Most in industry expected that this meant FDA would allow time to address concerns via new labeling,  bench testing, or simply the submission of additional data.  The veritable chasm between industry’s expectations as to how this process would play out and the reality espoused by FDA can be found in the close of the “Inadequate Validation” letter, which typically, allowed a sponsor a mere 24 or 48 hours to respond:

    [I]f the information you provide does not demonstrate that your device is adequately validated for its intended use and performing consistently, we may take steps as described in the guidance referenced above, including removing the test from the website listing of notifications, and may determine that the criteria for emergency use authorization have not been met. If such steps are taken and we make that determination, we would expect you to suspend distribution of your test, and we may request that you take additional actions to protect the public health as appropriate.

    One can imagine the feeling of despair when after months of waiting for a reviewer to be assigned to your EUA submission FDA returns with questions but only provides you with 24 or 48 hours to respond with the rationale that the timeline was in the “interest of public health.” Once on the notification list FDA has no way of checking to see if devices were actually introduced into the market, therefore, FDA approaches each review as if they have allowed the company to exist in the marketplace unchecked for months.  It seems that FDA is content with the idea that by limiting response windows to one or two days they are fulfilling their mandate to promote and protect public health.  Many companies are at a loss, however, as they are not prepared for this over-correction by FDA and simply cannot operate within such arbitrary timelines with draconian enforcement.

    We have to ask the question, “Is FDA intending for these companies to fail?” By now FDA should be well aware of industry’s plight.  Companies are waiting months only to scramble for 48-hours straight to try and deliver FDA the moon.  It behooves the Agency to publicly issue new instructions clarifying their expectations for companies on the notification list.

    In comparison, for a company that has submitted an EUA without being added to the notification list, FDA may not even specify a deadline to respond to the review team’s questions.  Furthermore, we have not observed an acceleration in the review timeline for companies on the notification list. It appears that you have everything to lose by being added to the notification list with nothing to gain.

    Prof. Hubert J. Farnsworth said it best “I’m sciencing as fast as I can.”  Only so much can be done in the span of 48 hours and many times FDA requests additional data or analysis. Bottom line: Companies should think twice before choosing to add their tests to the notification list.

    Categories: COVID19 |  Medical Devices

    “I Have A Little List”: CDRH’s Use of Public Lists and Notifications During the Pandemic

    The FDA is legally established as a law enforcement agency.  But its structure and activities have also generated its own “branding” as a trusted independent validator of medical devices.

    This public trust gives FDA tremendous power.  If a device has not undergone FDA’s premarket review (even if lawfully exempt), it often causes consternation among potential customers.  Likewise, if FDA issues negative public statements about the safety of marketed devices or the compliance status of a company, there can be a significant and lasting market impact.

    The use of this power is not new for FDA.  Historically, FDA has made public a variety warning letters about violations available to the public (and it continues to do so).  It also publicizes adverse event reports and  recalls, market withdrawals and safety notices. In Class I recalls, the agency may issue its own press release.  FDA issues device safety communications.  FDA makes public some information on inspection results.

    During the pandemic, however, CDRH has qualitatively increased its use of public lists and other information to leverage the FDA brand to protect the public health.

    A few examples:

    CDRH allows commercial manufacturers to distribute diagnostic test kits to perform assays to detect SARS-CoV-while the manufacturer is preparing its EUA request, provided that the manufacturer provides instructions for use of the test and posts data about the test’s performance characteristics on the manufacturer’s website.  CDRH is relying upon this “[t]ransparency to mitigate potential adverse impacts from a poorly designed test by facilitating better informed decisions by potential purchasers and users.”  The manufacturers and their tests are listed here, and the list expressly notes whether a test is “unauthorized” or “authorized.”

    This approach has not been an unalloyed benefit to manufacturers.  Some customers are unwilling to purchase products based upon notification and insist on waiting for an EUA to issue.  That reflects the power of FDA’s brand.  But other customers are perfectly happy to do so.  For instance, some sophisticated clinical laboratories may feel that they have an adequate ability to validate the tests and do not need to rely on FDA’s validation.

    As another example, CDRH maintains a list of tests that affirmatively should no longer be used or distributed here.

    As a third example, CDRH issued enforcement discretion guidance allowing thermographic cameras to be commercially distributed for detecting fever during the pandemic.  Upon finding that some firms are marketing the cameras in violations of the guidelines, FDA has issued warning letters.  That much is not unusual (except for the demand for a response within 48 hours).  But FDA also has redeployed these technical and legalistic warning letters into a plain English warning against using the products:

    FDA is advising consumers not to purchase or use certain products that have not been approved, cleared, or authorized by FDA and are being misleadingly represented as safe and/or effective for the mitigation, prevention, treatment, diagnosis, or cure of COVID-19. Your firm will be added to a published list on FDA’s website of firms and websites that have received warning letters from FDA concerning the sale or distribution of COVID-19 related products in violation of the Act. This list can be found at https://www.fda.gov/consumers/health-fraud-scams/fraudulent-coronavirus-disease-2019-covid-19-products. Once you have taken actions to address the sale of unapproved, uncleared, and unauthorized products . . . and any appropriate corrective actions have been confirmed by the FDA, the published list will be updated to indicate that your firm has taken such corrective actions.

    Other examples:

    SARS-CoV-2 Reference Panel Comparative Data | FDA (list of molecular tests and their performance against a reference panel).

    EUA Authorized Serology Test Performance | FDA (list of serology tests and their expected performance).

    Independent Evaluations of COVID-19 Serological Tests (Frederick National Laboratory for Cancer Research results of serology test performance – authorized and not authorized).

    As a final example, in response to a great deal of (often deliberate) misinformation circulating in the public domain about the meaning of “FDA registered” and “FDA certified,” CDRH has published an explainer.

    FDA took these steps in the crush of responding to the pandemic.  But they point to a broader potential after the pandemic.  We have gotten to the point where there has been wide and deep integration of internet-based research into business and consumer decision‑making.  It is now easy to quickly find FDA’s lists and other information they may put out.  For this reason, although the pandemic may have acted as a catalyst, FDA’s more aggressive use of publicity is likely to expand in the years to come.

    Congress should keep an eye on how FDA evolves its use of publicity in order to ensure that this power is used responsibly.  Still, Congress will no doubt appreciate that this approach permits FDA to achieve a public health impact more quickly and at lower cost than might otherwise be the case.

    Finally, the song title quoted in the title of this post is from Gilbert & Sullivan’s The Mikado.  The pertinent lyrics:

    “I’ve got a little list.

    I’ve got a little list.

    Of society offenders

    Who might well be underground

    Who never would be missed – who never would be missed!”

    Categories: Medical Devices

    New CDRH EUA Doorbuster! Validate a Point-of-Care or Rx Home-Use Device and You Have a Chance to Walk Away with a Brand New OTC Claim!

    On March 16th, 2021 CDRH announced a major policy change for the EUA program in an effort to expedite screening testing for the pandemic. Screening is the testing of asymptomatic individuals who do not have known or suspected exposure to COVID-19 in order to make individual decisions based on the test results.  This new supplemental template provides recommendations for device manufacturers with the goal:

    to streamline the authorization of screening tests with serial testing. The recommendations apply to test developers who seek an EUA from the FDA for certain screening tests prior to conducting certain performance evaluations with asymptomatic individuals.

    This is a major departure from previous policy as testing prior to authorization was only permissible in very limited cases for devices used only in High Complexity CLIA labs. It is important to note that this new pathway is only available to manufacturers of molecular and antigen tests.  Serology tests are not mentioned in this announcement.

    Serial testing as defined by FDA is the “testing the same individual multiple times within a few days.”  The thinking behind this strategy is the testing of a single patient across multiple days would increase the chances of detecting infection even when using devices with lower sensitivity.  FDA’s expectations for a device’s Sensitivity/Specificity increase when you traverse across the continuum of indications.  We provide an example for antigen tests below (Table 1).

    Table 1 – Performance Expectations by Indication in FDA’s EUA Templates (Antigen)

     CLIA LabPoint-of-CareRx-Only Home-Use (Symptoms Confirmed)Rx-Only Home-Use (Suspected Exposure)OTC Home-Use

    (Asymptomatic or No Suspected Exposure)

    PPA = Positive Percent Agreement; NPA = Negative Percent Agreement

    The key section of this announcement is where FDA identifies what indications may be eligible for this new program:

    For example, in certain circumstances, a [point-of-care] test or an at-home test could be authorized for over-the-counter (OTC) use without the need for validating its use in asymptomatic individuals prior to authorization.

    This statement has the potential to be both very powerful and very frustrating for industry.  In Table 2 below there is a breakdown of the data expectations for Point-of-Care, Prescription Home Use, and OTC Home Use with an asymptomatic claim.  What you can see from the information, in the various EUA templates laid-out in this fashion, is that ‘Prescription Home Use’ and ‘OTC Home Use’ are very similar in their requirements.  It is, therefore, reasonable to expect FDA to blur the line between ‘Prescription Home Use’ and ‘OTC Home Use’ when considering asymptomatic testing.  It was very surprising, however, to read that this new policy may also apply to devices validated for Point-of-Care.  The differences in data requirements between ‘Point-of-Care’ and ‘OTC Home Use’ are substantial.  Devices authorized for Point-of-Care are not validated to the same degree with respect to Robustness (Flex Studies), Human Factors (Human Usability), the data required to substantiate performance for Point-of-Care (POC) may have been largely retrospective testing.  This difference is due, in part, to the intended users – tests intended for POC are typically used by healthcare providers whereas home tests are used by lay people.

    The inclusion of Point-of-Care in this new policy implies that a manufacturer can take their authorized test, supplement the EUA with the additional information describing serial testing and obtain an OTC Home-Use indication. As of March 16, there are twenty (20) molecular EUAs and one (1) Antigen EUA with an attribute of ‘screening’ according to FDA’s website.  Of these tests, eight (8) are Direct-to-Consumer (DTC) and two (2) are Over-the-Counter (OTC). To date, there are no Point-of-Care EUAs with a screening attribute.

    Table 2 – Tests Recommended by FDA Stratified by Indication



    Point of Care (POC)Prescription Home UseOTC Home Use (asymptomatic)
    Limit of DetectionXXX
    Cross ReactivityXXX
    Microbial InterferenceXXX
    High Dose Hook EffectXXX
    Biotin InterferenceXXX
    Specimen StabilityXXX
    Test Kit StabilityXXX
    Control Materials (high-volume sites only)X
    SARS-CoV-2 Variant Analysis1XXX
    Point-of Care Clinical Agreement (Combination Prospective/Retrospective)X
    Flex Studies for Point-of-Care

    • Delay in Reading Time
    • Specimen Volume Variability
    • Buffer Volume Variability
    • Temperature and Humidity
    • Disturbance During Analysis
    Expanded Flex Studies for Home Use

    • 40°C and 95% RH
    • Delay in sample testing
    • Delay in operational steps
    • Delay in reading results
    • Sample volume variability*
    • Buffer volume variability*
    • Mixing/swab expression variability*
    • Disturbance during analysis
    • Placement on non-level surface
    • Impact of different light sources*
    • Hand-held, positioning at 90° angle
    Human Usability2XX
    All Comers Testing (Prospective)XX
    Self-Testing or Testing of Minors (Prospective)XX
    Discrepant AnalysisXX
    Asymptomatic TestingX
    1 FDA has announced plans to update the EUA Template, but has yet to do so for Antigen tests
    2 FDA expects 30 Participants for Rx Only and 100 Participants for OTC
    *If Applicable

    Supplemental Template for Developers of Molecular and Antigen Diagnostic COVID-19 Tests for Screening with Serial Testing (Example Template)

    The administrative section at the top of this new template echoes the announcement indicating that this policy applies to Point-of-Care indications:

    This template is intended to provide supplemental recommendations for developers of molecular and antigen tests seeking claims for screening with serial testing without studying asymptomatic individuals prior to authorization, including for point-of-care (POC) and at-home tests.

    While the intention of the policy is to increase testing availability FDA does not want manufacturers to misconstrue this as a paradigm shift with an opportunity to resurrect denied EUAs from the grave.

    These recommendations will generally not be applicable to developers with tests for which data has already demonstrated poor performance (e.g., less than 80% PPA) for testing asymptomatic individuals.

    FDA later goes on to seemingly contradict themselves on the next page of the template by stating:

    As discussed in the Antigen Template for Test Developers, strategies for serial testing with less sensitive tests (i.e., PPA <80%) may be able to be support authorization

    FDA gives the following example as a modification to the intended use:

    …individuals without symptoms or other epidemiological reasons to suspect COVID-19 infection, when tested twice over two (or three) days with at least 24 hours (and no more than 36 hours) between tests.

    As written, this implies that there is no expected modification to the intended use setting or user as a result of this policy change.

    The template does indicate that FDA intends to push as much of the clinical validation as possible to a post-marketing commitment in order to expedite the authorization of new tests.  While this recommended study size is small, 20 asymptomatic positives individuals, it has been increasingly more difficult to find asymptomatic positives naturally within the population, and that challenge is likely to continue to grow.  It is not clear from this template how long FDA will give these companies to compete these post-authorization studies.

    The template closes with a final recommendation for labeling:

    Proposed labeling should clearly identify the population in which the test’s performance has been validated, and clearly identify any populations included in the intended use for which the test’s performance has not yet been established and will be established during the above referenced post-authorization study.

    This final section further confuses what is expected of manufacturers as it implies that the post-authorization study is the only data requirement to expand the EUA claim to a new patient population.

    This announcement from FDA generates a rollercoaster of emotion starting with cautious optimism, to elation, and finishing with confusion. This policy raises major administrative questions that need to be answered in full if this new program is to have a chance at success.

    Can a manufacturer take an existing Point-of-Care or Rx-Only EUA and convert it to an OTC Authorization, if they commit to conducting an additional clinical study post-authorization?

    It is our review of the policy that, as written, it appears that the answer is yes. However, the policy never mentions the non-clinical tests that FDA typically requires for Home-Use tests and whether those will also need to be performed, either pre- or post-market, to support the expanded indication Point-of-Care authorized tests.  Without additional clarifications on the part of FDA, manufacturers will be left scratching their heads and unsure as to what FDA expects in EUAs moving forward.

    The next “FDA Virtual Townhall” is Wednesday March 24th at 12:15 pm (ET).  See you there.

    Categories: COVID19 |  Medical Devices

    Potential False Results with Roche Molecular Systems’ SARS-CoV-2 Assay

    On Friday, March 12th FDA posted a letter to healthcare providers about performance concerns regarding the Roche Molecular Systems, Inc. cobas SARS-CoV-2 & Influenza Test for use on cobas Liat System.  This public letter appears to be the culmination of a dialogue between Roche and FDA.  Roche’s root cause analysis investigation has identified two potential causes for the false positives:

    • Roche identified that the assay tubes may sporadically leak, causing an obstructed optical path in the Liat analyzer, producing abnormal PCR growth curves. This could lead to invalid or erroneous positive results, particularly for the Flu B test. If a tube leak occurs, later testing runs may have an increased likelihood of false positive Flu B results.
    • Roche determined that abnormal PCR cycling in the reaction tubes may also produce abnormal PCR growth curves, leading to erroneous results. The issue is sporadic and may be caused by multiple factors happening at the same time, such as hardware positioning, volume movement, and curve interpretation. This issue may cause false positive results for multiple analytes (Influenza A, Influenza B and/or SARS-CoV-2) in a single testing run.

    In response, FDA recommended three actions by users:

    1. Monitor for unexpected clusters of positive Flu B results, as this may indicate the cobas Liat System has experienced a tube leak.
    2. Repeat tests when two or three analytes are positive. Different results on the repeat test may indicate abnormal PCR cycling.
    3. Stop using the cobas Liat System and contact Roche if you suspect either of these two issues has occurred.

    This letter is not the first FDA has posted for Clinical Laboratory and Point-of-Care staff.  It is actually the fourth one since October 2020 and the eighth such notice flagging in‑vitro diagnostic performance issues or concerns during the pandemic.

    These notices have hit each of the three major classes of in-vitro diagnostic products used for the nation’s pandemic response, PCR, Serology, and Antigen Tests.  Here are three relatively recent examples:




    The full list of FDA’s “Letters to Health Care Providers” can be found here.

    As we proceed through this pandemic, it is becoming more critical that manufacturers be as vigilant as ever with post-market surveillance to flag performance issues early in order to be able to investigate and identify potential root causes.  Prompt investigation and correction is always preferable to pulling a test that works out of the marketplace.  It is in no one’s best interest to lose testing capacity and we hope that FDA is affording companies of all sizes the same opportunity that Roche has been given to investigate and correct rather than be forced to pull an assay from distribution.

    The Biden Admin Announces Expansion of COVID Testing with New Funding – “Living in a Material World”

    On February 17th, 2021 the Biden Administration announced an expansion of the Federal strategy to test the population for SARS-CoV-2 with a three pronged approach:

    1. Expand COVID-19 testing for schools and underserved populations ($650 Million);
    2. Ramp up the domestic manufacturing of testing supplies and raw materials ($815 Million); and
    3. Increase genomic sequencing of the virus to better prepare for the threat of variants ($200 Million).

    Each of these goals requires significant and targeted investment at all levels of the diagnostics supply chain from testing locations to finished device manufacturers to the suppliers of raw materials.

    The administration has set aside a total of $1.665 billion dollars across all three initiatives. The $650 million dollar investment into new testing is intended to translate into 25 million new tests delivered monthly to regional hubs across the US that are under the auspices of DoD and HHS.  It is not clear from the administration’s announcement what the total number of tests that are expected to be realized by this investment, but the news is still overwhelmingly positive for manufacturers still working their way through the EUA process. This initiative puts an emphasis on targeted testing of the population that will occur outside the traditional laboratory setting. This is consistent with a shift in FDA’s focus for diagnostic tests from CLIA Lab runs assays to non-laboratory sites such as Point-of-Care and Home Use. HPM recently released a blog post on FDA’s changing priorities (“Beware EUA Deprioritization”)

    The lion’s share of the monies ($815 million) is slated for domestic manufacturing of testing materials.  Specifically, filtered pipette tips, nitrocellulose, and injection molded reagent container closures. This additional investment is heartening news as many manufacturers have experienced delays in device development over the last 12 months that are directly traceable to the ability to source samples, reagents, controls, and basic testing supplies.  The infusion of federal money toward domestic manufacturing may favor EUAs that bolster the domestic supply chain.

    The final pool of monies ($200 million) is slated to address an ever-increasing concern for the pandemic which is the mutation of the SARS-CoV-2 virus and the rise in new mutant strains that may impede our march toward herd immunity and a return to normalcy. This increased funding for virus sequencing may aid in the rapid identification of new variants and allow for the development of multi-valent vaccines or boosters to maintain the efficacy of the vaccination program.  This money will likely not impact the EUA work that the Center for Devices and Radiological Health is doing in the review of new diagnostic EUAs.

    This announcement comes amidst a series of public notices and statements from FDA regarding their concern with genetic mutations of the virus impeding the performance of diagnostic tests. On February 4th 2021, FDA provided a “Coronavirus (COVID-19) Update” where the agency stated:

    For diagnostics, we have been monitoring for new mutations, identifying and working with developers of tests whose performance may be adversely impacted by them, and communicating with the public when helpful information becomes available. At this time, we believe the risk that the currently known mutations will impact overall testing accuracy of molecular tests is low. Moving forward, we are considering expanding the role of in silico monitoring by sponsors prior to and following authorization to assess for mutations that impact the performance of the test, test designs to minimize the impact of new mutations and ways to label authorized products to be transparent about what we know the test can detect.

    This update was followed-up later in the month on February 22nd, 2021 with a new policy “Policy for Evaluating Impact of Viral Mutations on COVID-19 Tests.”  With issuance of this policy statement, FDA is putting industry on notice that due to the rise of mutations, post-authorization monitoring of assay performance will be a key consideration for an EUA. In this policy FDA states:

    During FDA’s review of an EUA request for a COVID-19 test, FDA intends to consider the performance of the test across all known variants, as well as the developer’s plans for post authorization monitoring.

    For industry, the only way to keep up with new mutations is to run an analysis through a sequence database, like the one maintained by the National Center for Biotechnology Information (NCBI). It is expected that this increased funding will improve the quality of databases that are used to monitor the pandemic and that industry uses to evaluate inclusivity of their tests.

    In this policy update, FDA also gives granular feedback to industry on FDA’s expectations for developers of molecular diagnostic tests. However, the feedback for developers of Serology and Antigen tests is high level with more feedback from the Agency being promised in future updates to the EUA templates.  In light of FDA’s policy, companies with pending EUAs or those who are in the process of preparing their submissions to FDA should be proactive and develop plans for the evaluation of mutations as FDA has applied new thinking and requirements retroactively to EUA reviews.

    Categories: COVID19 |  Medical Devices

    When Is Skinny Not Skinny Enough?

    Perhaps when you’re carving out a patented method of use?  Well, at least that’s what GSK is arguing.  As the now-infamous GSK v. Teva case makes its way through the Federal Circuit once again to address what many have called the death-knell to skinny-labeling (also called a “section viii statement” or a “carve-out”), Teva is poising for a fight to save the practice.  Framing the issue in the Petition for Rehearing briefing, Teva, like much of the generic industry, argues (with support from former Rep. Waxman) that the Federal Circuit decision upends the statutorily-enacted Hatch-Waxman carve-out.  GSK, on the other hand, characterizes the issue as a fact-specific inquiry into whether Teva’s generic carvedilol adequately carved out enough of a patented method-of-use included in GSK’s Reference Listed Drug (“RLD”) Coreg’s labeling.  The Federal Circuit reheard arguments on this case in February 2021.  And, as we wait for a new opinion that could have huge implications for generic drugs, we bring this (belated) update.

    To jog your memory: In October 2020, the Federal Circuit issued a big blow to the generic drug industry when it reinstated a jury verdict awarding GSK $235 million in damages from Teva resulting from the generic company’s alleged “induced infringement” of a GSK patent through skinny-labeling.  As we explained back in October, the Hatch-Waxman Amendments permit generic drug companies to “carve-out” a patent-protected method-of-use included in the labeling of the RLD so long as such a carve-out does not compromise the safety or effectiveness of the product for the conditions of use remaining in the labeling.  The resulting “skinny-labeled” generic can still be listed in the Orange Book with an “A” therapeutic equivalence code because such ratings look only to the drug product itself rather than the approved indications.  As a result, a skinny-labeled “A”-rated generic drug can be, and indeed automatically will be, substituted for the brand drug regardless of the reason the product is prescribed.  Effectively, GSK argues, even though the statute provides for such a carve-out, even though FDA’s Orange Book states that the generic is therapeutically equivalent to GSK’s product, and even though the pharmacy is legally required to substitute an AB-rated generic for brands in most states (absent doctor’s orders otherwise), the mere truthful promotion of Teva’s skinny-labeled version of GSK’s Coreg (carvedilol) as AB-rated constitutes induce infringement.  And, for all intents and purposes, both the jury and the Federal Circuit agreed, making sweeping statements indicating to industry that even the carved-out label may be enough to induce infringement (“[p]recedent has recognized that the content of the product label is evidence of inducement to infringe”).

    Understandably, the Federal Circuit decision led to a panic in the generic industry.  Skinny-labeling has been around for decades—countless generic drugs have marketed their skinny-labeled drugs as therapeutically equivalent to their Reference Listed Drug.  Now, even though some of those patents have expired and carved-out language added into the generic labeling, there’s no telling how many cases for induced infringement may be in the wings.  Given this uncertainty in the industry, many have expressed concern about whether generic drug sponsors will proceed with patent carve-outs and whether any resulting hesitancy will result in increased drug prices.

    It is no surprise then that Teva promptly petitioned the Federal Circuit for a rehearing en banc.  Framing the issue as “whether induced infringement can be used to nullify a provision of the Hatch-Waxman Amendments,” Teva argued (as many in the press have) that if describing a skinny-labeled product as the generic equivalent of the RLD “can be inducement, as the majority held, every skinny-labeled generic is at risk, and the carve-out statute is a dead letter.”  GSK, on the other hand, opens its Response to Teva’s Petition with a strong statement: “This case does not implicate the fate of section viii carve-outs.”  Instead, GSK explains, that the case is much narrower than Teva portends as it “merely reaffirmed that section viii is not a get-out-of-jail-free card for generics who do not fully carve out the patented use from their labels.”  GSK explains that Teva did not thoroughly carve out all of GSK’s patented use, and it’s the label’s claims that induced infringement, not the AB-rating promotion.  GSK concedes that the Federal Circuit opinion never actually noted that the “partial label instructed the patented method,” but argues that “that finding is implicit in, and necessary to, its decision.”   

    On February 9, 2021, the Federal Circuit vacated the October 2, 2020 judgment and withdrew the controversial opinion.  The Federal Circuit granted a panel rehearing (rather than en banc), which occurred on February 23, 2021.  But rather than address the overarching issue of induced infringement by way of skinny labeling, the Court limited the appeal—or at least the rehearing—to evidence to support the jury verdict of induced infringement.  In other words, the Court declined to address whether skinny-labeling itself is induced infringement and theoretically will look only to the specific promotion used to allegedly induce infringement.  This limitation could provide for a much narrower decision than the October 2, 2020 decision, but the Court did leave room for itself to make a broader decision, stating that “[w]e find all other issues to be sufficiently briefed.”

    While FDA did not submit an Amicus Brief, Henry Waxman—the namesake of the legendary Hatch-Waxman Amendments that created the skinny-label practice—did.  Others joined Rep. Waxman in submitting Amicus Briefs, including Apotex, Novartis, Mylan, a consortium of professors, Knowledge Economy International, the Association for Accessible Medicines, and the R Street Institute in support of Teva.  These briefs focused on the policy aspects—health, economic, and patent policy.  No Amicus Briefs were filed in support of GSK or the Federal Circuit’s decision.

    The Federal Circuit reheard the case on February 23, 2021.  From all accounts, the panel listened to the narrowed questions about the facts at issue here (i.e., whether Teva’s skinny-labeled carvedilol carved out enough language) rather than the overarching concerns about the death of the carve-out.  This makes sense given the parties and the venue: a patent case should be specific to the patents-at-issue, not a validation of a statutory provision.  However, we can’t help but think about the arguments that might arise if this case were strictly about statutory interpretation.  How would the Court reconcile the implicated conflict between the patent statutory scheme (induced infringement) and the Hatch-Waxman Act (carve-outs)?  Obviously, patent and FDA cases overlap often: innovation is critical to the drug industry and patents are critical to innovation, thus ANDA litigation, 30-month stays, etc.  But, effectively, this case would force the Courts to determine whether to protect innovation or whether to protect accessibility—the very balance that Congress sought to achieve in adopting the Hatch-Waxman Amendments.  Given the limited oral argument, it’s unlikely that the Federal Circuit will go that far in this case, as it will probably issue a very narrow decision that allows the skinny-label to live another day, but the Federal Circuit did leave room to address the entire issue.  But all we can do now is wait to see if the Federal Circuit believes that Teva’s carvedilol labeling was skinny enough or whether the Federal Circuit’s initial decision applies more broadly.

    If You Want It Done . . . Bill to Facilitate Marijuana and CBD Research Re-Introduced in the Senate

    The Senate recently reintroduced legislation that would promote research into medical use of marijuana.  The legislation would also importantly correct a deficiency in prior law and the Drug Enforcement Administration’s (“DEA’s”) recent rulemaking related to synthetically derived CBD.

    Marijuana remains classified as a schedule I controlled substance under the federal Controlled Substances Act.  Because drugs in schedule I are defined to have “no currently accepted medical use in treatment in the United States,” distribution except in very limited circumstances of any product containing marijuana remains illegal at the federal level.  21 U.S.C. § 812(b)(1)(B).  To date, only certain drugs containing THC such as Marinol, and hemp-derived CBD with less than 0.3 percent delta-9-tetrahydrocannabinol (“THC”) have been excluded form Schedule I.  Yet despite federal law, 36 states and the District of Columbia have authorized the manufacture, distribution and use of marijuana and/or its constituents including THC and cannabidiol (“CBD”) for a wide-range of differing medical indications.

    We reported in January how after more than four years DEA finally issued its final rule on registering additional manufacturers of marijuana for research.  (For our post, see The Long and Winding Road: DEA Issues Final Marijuana Registration Rule, Jan. 8, 2021.)  Congress, however, has not been sitting idly with respect to cannabis research.  Senators Dianne Feinstein (D-CA), Chuck Grassley (R-IA) and Brian Schatz (D-HI) re-introduced a bill with bipartisan support in the Senate that seeks to expand medical research with marijuana and CBD by removing some of the restrictive regulatory roadblocks.  The Senate unanimously passed an identical bill during the waning days of the last Congress.  Senator Feinstein, re-introducing the Cannabidiol and Marihuana [sic] Research Expansion Act on February 4th observed, “If the science shows that marijuana and its derivatives, including CBD can effectively treat serious medical illnesses, we should enable products containing these substances to be brought to the market with FDA approval.  But in order to make this determination, we must reduce the barriers currently impede important research.”  Feinstein, Grassley, Schatz Introduce Bill to Expand Cannabidiol, Marijuana Research, Press Release, Feb. 5, 2021.

    The bill, S. 253, would promote cannabis research by requiring the Attorney General (by delegation, DEA) to register researchers if Health and Human Services (“HHS”), National Institutes of Health (“NIH”), or another federal agency that funds scientific research reviews and approves their research protocol and they employ adequate security measures to prevent diversion.  DEA would have to approve registration applications or request supplemental information within 60 days, then approve or deny registrations within 30 days after receiving supplemental information.

    The bill would also expedite the process to increase the quantity of cannabis for research and facilitate protocol changes without requiring researchers to reapply.  Researchers seeking to increase drug quantities would only have to notify DEA instead of both DEA and FDA.  Researchers seeking to amend approved protocols involving changes to drug quantity or type, its source or storage, tracking or administration conditions must only notify DEA at least 30 days before implementation.  Their request would be deemed approved unless DEA objects within 30 days.  The agency can only object if additional security safeguards are required.  HHS would maintain authority over research protocols, including changes in administration, dosing and number of patients.  The bill requires DEA to issue regulations related to these changes within a year.

    In addition to requiring DEA to process cannabis researcher applications within a certain timeframe, the bill imposes time constraints by when the agency must move on bulk marijuana manufacturer applications.  For bulk marijuana manufacturers, DEA would have to approve or request supplemental information for applications to manufacture for research solicited in the Federal Register within 60 days of receiving an application, then approve or deny the application within 30 days of receiving required supplemental information.  Requiring DEA to move on marijuana manufacturer applications is a welcome advancement of the registration process as some of the 38 marijuana manufacturer applications received by DEA lingered for four years after the agency announced that it would issue additional registrations in August 2016.

    The bill streamlines development of FDA-approved drugs using marijuana and CBD by:

    • Allowing accredited universities and medical schools, practitioners and manufacturers with a schedule I registration to manufacture, distribute, dispense and possess marijuana for medical research aimed at drug development or commercial production;
    • Requiring DEA to license manufacturers and distributors for the commercial production of FDA-approved marijuana or CBD drugs; and
    • Allowing DEA-registered institutions to import or export marijuana or CBD to conduct medical research for drug development.

    Within one year of enactment, HHS must report to Congress on potential therapeutic effects of marijuana and CBD on serious medical conditions, and their effects on the human body, the adolescent brain, and on cognitive abilities, including the ability to operate vehicles and heavy equipment.  HHS will also report on the research barriers of marijuana grown in states that have legalized its use, and recommend how to overcome them.

    The bill would allow physicians to discuss the potential harm and benefits of marijuana derivatives like CBD, as treatment with patients.

    The bill also corrects a non-sensical interpretation stated in DEA ‘s August 21, 2020 interim final rule that non-plant, synthetic CBD is a schedule I substance regardless of whether its THC content on a dry weight basis is at or below the 0.3% level for non-controlled hemp-derived CBD.  The bill would amend the definition of marijuana in the CSA to exclude the synthetic equivalent of hemp-derived CBD containing less than 0.3% THC.  It makes no sense to treat synthetic CBD as a schedule I controlled substance when its abuse potential, little as it may be, is less than hemp-derived CBD.  The bill would allow researchers and others to handle synthetic CBD without having to comply with DEA registration, recordkeeping and security requirements.

    A number of organizations support the bill including the American Medical Association, American Academy of Pediatrics, American Society of Addiction Medicine, Friends of the National Institute on Drug Abuse, National Cannabis Industry Association and the National Organization for the Reform of Marijuana Laws.

    The bill has been referred to the Committee on the Judiciary.

    Higher Medicaid Rebates Will Help to Fund COVID Rescue Plan

    Last Thursday March 11, the American Rescue Plan Act of 2021 was signed by President Biden.

    Out of the hundreds of pages of this COVID relief legislation, our pinpoint focus here is on several pages relating to Medicaid coverage and drug rebates.  The legislation requires Medicaid and the Children’s Health Insurance Program (CHIP) to cover COVID-19 vaccines, vaccine administration, testing, and treatments, without cost sharing, for all eligible beneficiaries during the public health emergency and for one year after it ends.  Sec. 9811(a)(1), (2).  The legislation also makes clear that COVID therapies and preventive measures are subject to rebates under the Medicaid Drug Rebate Program if they are “covered outpatient drugs” as defined in the Medicaid Drug Rebate statute.  Sec. 9811(a)(4).  As with other vaccines, COVID-19 vaccines remain excluded from the Medicaid Drug Rebate Program.  Sec. 9811(a)(4).

    A question arises whether an unapproved drug authorized under an emergency use authorization (EUA) is a covered outpatient drug subject to Medicaid rebates.  Under a literal reading of the definition of a covered outpatient drug, such a drug must be approved under section 505 or 506 of the FDC Act or section 351 of the Public Health Service Act.  An EUA is authorized under section 564 of the FDC Act and is not an approval pursuant to those provisions.  However, in a somewhat related context, CMS has suggested that an EUA is an “approval” under the FDC Act.  COVID-19 Frequently Asked Questions (FAQs) for State Medicaid and Children’s Health Insurance Program (CHIP) Agencies, p.18, fn. 3.   Hopefully CMS will provide guidance on this point.

    Of broader consequence to drug manufacturers generally, effective January 1, 2024, the legislation sunsets the cap on the total Medicaid unit rebate amount that was instituted by the Affordable Care Act.  Sec. 9816.  (The House version of the bill had this change taking effect January 1, 2023, but the effective date for the change was extended by one year by the Senate.)  The total calculated Medicaid rebate amount is comprised of the basic rebate and the additional rebate, which is a penalty imposed for raising a price at a rate greater than the rate of inflation.  Without a cap, the rebate can be more than the average manufacturer price (AMP) of the drug.  The Affordable Care Act capped the rebate at 100% of the AMP so that a manufacturer would not pay a higher rebate for a drug than its AMP.  According to the House Report, CBO estimates that eliminating this cap will increase the amount of rebates that manufacturers pay Medicaid and will reduce direct spending in Medicaid by $15.9 billion over the 2021-2030 period.

    Categories: Health Care

    Keeping Up With the Kardashians – OPDP Edition

    I would be lying if I said I hadn’t expected this most recent OPDP Untitled letter.  OK, maybe not THIS letter.  Some background: Back in November 2020, after an article was published about the ethical questions surrounding “Sponcon,” (sponsored content – for those not hip to the lingo), I pulled up Khloe Kardashian’s Twitter feed to check out her recent ad for Nurtec ODT.  I stared at the ad, and then spent an embarrassingly long amount of time debating with myself as to whether placing scrolling ISI right below Khloe Kardashian’s bust made it more OR less likely to be noticed.  I passed my phone to my husband and asked him to tell me about the Nurtec ODT safety information.  Eyes glazed, he responded, “there’s safety information?”  I had my answer.

    This most recent OPDP letter (the first Untitled Letter of 2021), objects to a sponsored video – and is similar to OPDP’s last Warning Letter to CooperSurgical.  Parallels between the two letters include the offending material being a sponsored video (not otherwise re-distributed by the company on different platforms), no Form 2253 submission, and complaints lodged through FDA’s Bad Ad program.

    This letter is significant for a number of reasons (not the least of which is that I now can’t simply refer to the “Kardashian Letter” as it may create confusion about which letter I’m referencing).  What’s fascinating (to me) is that OPDP includes in second place its allegations that risks were minimized in the video, prioritizing the offending efficacy claims.  And what are those efficacy claims?  The first of which is that Nurtec ODT “works in about 15-30 minutes.”   The second is that Nurtec ODT was a “gamechanger” and “other medications would give me rebound headaches, and this one doesn’t . . .”

    In 2012, an Untitled Letter based on these claims would be expected.  But in 2021, given the significant drop in OPDP enforcement letters and post publication of FDA’s Guidance on Medical Communications Consistent with the FDA-Required Labeling (Guidance), are these the type of claims to trigger an OPDP Untitled Letter?  The claims, themselves, seem awfully similar to specific examples FDA includes in its Guidance, which permits product communications consistent with the FDA-required labeling even if those communications are not based on substantial evidence.  From the FDA Guidance:

    Q.4.        What are examples of the kinds of information that could be consistent with the FDA-required labeling for a product?

    A.4.        The following are examples of some general types of information that could be consistent with the FDA-required labeling. . . Information based on a comparison of the safety or efficacy of a medical product for its approved indication to another medical product approved for the same indication . . . Information about the onset of action of the product for its approved indication and dosing/use regimen (e.g., the FDA-required labeling for a product approved to treat major depressive disorder does not contain information about onset of action before the point in time designated as the study’s endpoint, and a firm’s product communication provides information indicating that the product shows an effect relative to the control at 2 weeks).

    So what happened here?  What happened seems to be the absence of any evidence to support Ms. Kardashian’s claims other than her personal experience.  Consistency with the FDA-required labeling is not the only factor to consider when determining whether a communication is truthful and non-misleading.   Claims must still be supported by evidence that is scientifically appropriate and statistically sound.  “The amount and type of evidence needed to support a particular CFL promotional communication depends in part on the topic addressed by the communication. For example, different evidence would be needed to support a long-term efficacy presentation than would be needed to support a presentation about a product’s mechanism of action. The amount and type of evidence needed also depends on the particular representations or suggestions that are made about any given topic in the communication.”  Guidance at 12.  Therefore, despite these claims representing a truthful experience for Ms. Kardashian, the letter points out that they are misleading because OPDP is unaware of any data that supports these statements, generally.

    OPDP further cites the video as misleading “because it fails to present information relating to the contraindications, warnings, precautions, and adverse reactions for Nurtec ODT with a prominence and readability reasonably comparable with the presentation of information relating to the benefits of Nurtec ODT. Specifically, the video contains claims and/or representations about the benefits of Nurtec ODT in the audio portion, while the risk information is presented in text only format and in small font. Moreover, the risk information only appears briefly for four seconds at the end of the video, after the close of the Spokesperson’s presentation, where it is unlikely to draw the viewer’s attention.”   OPDP’s views as expressed in this letter are not new; 21 C.F.R. §202.1(e)(1) provides that advertisements broadcast through media such as radio or television include information relating to the major side effects in the audio or audio and visual parts of the presentation.  It is not sufficient to have safety information presented solely on screen when efficacy is provided through audio.   Content and format considerations with regard to presenting risk information in broadcast promotional material has been an issue reiterated in FDA’s (Draft) Guidance on Presenting Risk Information and has also been the subject of OPDP research.

    Circling back to initial perceptions about the similarities between this Untitled Letter and the recent CooperSurgical  Warning Letter, it’s notable that both relate to TV broadcast videos that were “sponsored” by the company, not re-distributed on other platforms, and not submitted to FDA on Form 2253.  With the increasing number of television shows that allow third parties to sponsor content, industry should be particularly cautious when availing itself of these opportunities.  Depending on the context, interviews with your spokespeople and sponsored TV/News segments about your products may subject you to liability even if you are not in complete control over the content and do not otherwise re-distribute it.

    FDA Warns Against Use of Registration Certificates: It Don’t Mean A Thing

    It’s not just drug companies that push the limit on marketing their products – see our posts about recent OPDP warning letters.  Medical device companies are fighting for any edge to differentiate their products too.  Even before COVID-19 brought an onslaught of new players to the FDA-regulated space, many sophisticated medical device companies used to include FDA’s logo on marketing materials to imply that FDA had endorsed their products.  The misuse of the logo became so pervasive that FDA issued an official “FDA Logo Policy,” which warns that “[u]nauthorized use of the FDA logo may violate federal law and subject those responsible to civil and/or criminal liability.”  Despite this threat, FDA continues to cite companies for misuse of the logo.  See, e g., Warning Letter issued to Silkprousa LLC (Aug. 18, 2020) (“Your device is also misbranded under section 502(a) of the Act, 21 U.S.C. § 352(a), because your labeling on the package of your device and your website uses the FDA logo.  The FDA logo is for the official use of the FDA and not for use on private sector materials.”).

    The COVID-19 pandemic has caused companies to exercise even more creative license in an attempt to differentiate products that might otherwise appear interchangeable (e.g., 3-ply disposable face masks).  We have seen the advent of the “FDA Registration Certificate,” which looks like an official government document, and sometimes includes the FDA logo (illegal by itself), the establishment registration number, or a screenshot of the FDA establishment registration database showing the company’s registration status.  Any savvy FDA lawyer knows that registration alone does not convey information about the company or product’s regulatory compliance status, and certainly does not imply FDA approval or endorsement of a product, but not all of us can be savvy FDA lawyers.

    On March 3, 2021, FDA announced that it had told 25 companies that produce these so-called “FDA Registration Certificates” to stop issuing them.  We have not yet seen the letters FDA issued to the certificate-producing companies, and it’s unclear whether FDA will follow-up with enforcement action if these companies fail to cease distribution of these documents (and if so, on what grounds).

    In conjunction, FDA released a new webpage titled “Are There ‘FDA Registered’ or ‘FDA Certified’ Medical Devices?  How Do I Know What is FDA Approved?”  Spoiler alert: the answer to the first question is No. The key points FDA highlights are:

    • When a facility registers its establishment and lists its devices, the resulting entry in the FDA’s registration and listing database does not denote approval, clearance, or authorization of that facility or its medical devices.
    • The FDA does not issue any type of device registration certificates to medical device facilities.
    • Firms that misleadingly display certificates alongside information about and photos of a device for sale in the United States to imply review or approval by FDA of the device misbrand the device in violation of the Federal Food, Drug, and Cosmetic Act.

    FDA also provided detailed directions for identifying a product’s status – whether it has been approved or cleared, or authorized under an Emergency Use Authorization.  Circling back to the grammatically curious title of this blog post, FDA’s point is that registration “don’t mean a thing” “if it ain’t got that” 510(k) clearance, PMA approval, de novo classification or EUA authorization – not as catchy as when Ella Fitzgerald and Duke Ellington sing it.

    Categories: Medical Devices

    HP&M’s Food, Beverage & Supplement Wrap Up: February 2021

    Welcome to the latest edition of Hyman, Phelps & McNamara, P.C.’s monthly wrap up of food, beverage and supplement news, including regulations, guidances, events, and whatever else is catching our eye.

    Food & Beverage

    • Transition: As of this writing, Janet Woodcock is Acting Commissioner of Food and Drugs; Norris Cochran is Acting Secretary of Health & Human Services; and Tom Vilsack was just confirmed as Secretary of Agriculture (again!).
    • 3D printed ribeye? An Israeli company unveiled what is being described as a “3-D printed rib-eye” made with  “3-D bioprinting technology.” The company claims to have been in discussions with USDA and FDA for the past two and a half years.
    • Food Supply Chain Focus at the WH. The President signed an Executive Order to help create more resilient and secure supply chains for critical and essential goods, and agricultural commodities and food production are a key sector that will be the focus of a year-long review.
    • Keep those essential workers safe! FDA published a new web page with information to help employees in the food and ag sector communicate about COVID-19 vaccines in their workplace.
    • Prop 65: OEHHA announced a (virtual) public hearing on March 11, 2021, at 10:00 a.m. and extended the time for submitting comments to the proposed rule regarding short form warnings to March 29 to accommodate the hearing.
    • Baby food report. The House Subcommittee on Economic and Consumer Policy, Committee on Oversight and Reform released a report alleging “dangerous” levels of heavy metals in baby foods. Shortly thereafter, FDA published a response in the form of a Constituent Update in which the agency assured the public that “FDA regulations and monitoring help to ensure the safety of baby foods sold or manufactured in the United States.”
    • US Food Supply is Safe! FDA and USDA issued a statement that food and food packaging have not been linked to spread of COVID-19.
    • Costs of Foodborne Illness: USDA published a report on the cost of foodborne illnesses; the report is a bit short on conclusions but the cost continues to increase. This is not particularly surprising since last year CDC reported a continued increase in incidence of foodborne diseases.
    • Speaking of Pathogens in Food: Center for Science in the Public Interest together with several other public interest organizations and individuals submitted a petition to FSIS/USDA requesting that FSIS engage in rulemaking to 1) establish enforceable finished product standards for Salmonella types of greatest public health concern and Campylobacter and 2) require poultry establishments to identify and control food safety risks within their supply chain. FSIS opened a docket on regulations.gov for comments which must be submitted by April 6, 2021.
    • Organic wild caught fish? NOP just announced a town hall meeting regarding wild caught fish.


    • More transition. Steven Tave is leaving the Office of Dietary Supplement Programs and moving to the Office of Regulatory Affairs at FDA.  Cara Welch will be acting director of ODSP starting March 15.
    • Warning Letters. FDA issued warning letters to 10 companies for selling dietary supplements that claim to treat depression and other mental health disorders.
    • Criminal Sentencing. A former dietary supplement company executive was sentenced to prison for his role in fraudulently selling popular workout supplements that caused liver damage.  A number of executives have already been sentenced in this ongoing fraud investigation.
    • Nanotech-related claim requires substantiation. NAD recommended discontinuation of a claim touting a nanotech oral delivery system for glutathione as the first effective alternative to injections. NAD found the supporting in vitro and in vivo pilot studies did not constitute a reasonable basis for the claim.

    More on Cannabis

    Coming up:

    • The deadline for submission of comments on labeling of cell-cultured seafood products is coming up on March 8.
    • The American Conference Institute’s popular “FDA Boot Camp” – now in its 36th iteration – is scheduled to take place (virtually, of course) March 24-25, 2021, and is co-chaired by HPM’s own Kurt Karst.
    • Riëtte van Laack will be discussing “Nutrient Content, Health and Other Claims” at FDLI’s Introduction to Food Law and Regulation, March 16-18.


    Area of Interest Funding – “There’s Always Money in the Banana Stand”

    If you tuned in to FDA’s weekly Virtual Town Hall Meeting on February 10th, 2021 you would have seen a short presentation by Toby Lowe (CDRH/OHT-7) describing a recent funding announcement from HHS OASH, Office of Assistant Secretary for Health, and the DoD. This “Area of Interest” (AOI) funding announcement is a call for proposals from industry.

    you may request investment funding for capacity expansion and provide price quotes for raw materials, test components, supplies, et cetera for COVID-19 point-of-care tests and other IVDs. This is an expedited process that’s coordinated by HHS and OASH and DoD to support the government’s COVID-19 response to rapidly increase manufacturing capabilities within the diagnostic supply chain.

    This funding announcement is not a unique occurrence, in fact, there is a whole group at HHS with a mandate to expand testing supplies and testing capacity through targeted investments.  The COVID-19 Testing and Diagnostic Working Group (TDWG) has been built around four central goals:

    • Understand the diagnostic supply chain, including projected production and potential constraints and bottlenecks;

    • Work with state public health and laboratory leadership, diagnostics manufacturers, and commercial labs throughout the country;

    • Provide technical assistance to leverage existing testing infrastructure and resources based on available tests; and

    • Distribute certain testing supplies, focusing primarily on point-of-care technologies, to support states’ testing goals.

    This funding announcement is yet another indication, in a string of recent public statements and actions on the part of FDA, that the federal government is shifting time, energy, and resources from the CLIA Lab base testing to testing in non-laboratory settings, like Point-of-Care and people’s homes.  HPM recently released a blog post on FDA’s changing priorities (“Beware EUA Deprioritization”).

    A link to the funding announcement can be found here.  The deadline to apply is March 7th.  (And for those Arrested Development fans, we’ll end with a link to the Banana Stand.)

    OPDP Issues Second Warning Letter of 2021. But Wait, Where Did the OPDP Warning Letters Go?

    Well, it’s been busy for OPDP (and the Rx Ad/Promo bloggers over at the FDA Law Blog).  After getting off to a slow start in 2021, OPDP issued yet another Warning Letter, apparently the day after its first.  Unlike the first letter, this OPDP Warning Letter to CooperSurgical appeared “quietly” on FDA’s general Warning Letters page, and without the accompanying fanfare of a CDER press release and Twitter campaign (as we blogged about previously).  When checking the status of OPDP’s Warning Letters page, we were surprised (shocked, really) to see that all Warning Letters had been removed and the page had been updated to reflect only Untitled Letters.  We’re not happy with this development – having OPDP letters in a single location was incredibly useful when evaluating enforcement trends.

    This newest Warning Letter about a video for Paragard (intrauterine copper contraceptive), ticks off several OPDP priority boxes – the product has a broad patient base with a video (airing on TV) that could be considered a wide-reaching promotional campaign, CooperSurgical was the subject of a previous OPDP letter for similar product promotion, and the video was brought to OPDP’s attention through the FDA Bad Ad program.

    The offending video, entitled “Paragard: Family Planning During The Pandemic,” is no longer available, but appeared on WBTS’s The Hub Today, a Boston lifestyle and entertainment show.  FDA states that CooperSurgical failed to submit a copy of the video at the time of initial dissemination under cover of Form FDA-2253, and FDA’s description of the issues is short and to the point.  The video is described as providing claims and representations about the uses and benefits of Paragard, but failing “to communicate any risk information about the product.”  FDA specifically notes that referring viewers to the product specific website for further information did not mitigate the “complete omission” of risk information from the video.

    CooperSurgical previously received an Untitled Letter in 2019 for a Paragard DTC TV advertisement for omitting important risk information.  OPDP so notes in this letter, stating that the new video appears to promote Paragard without presenting the serious risks in truthful and non-misleading manner, “despite concerns previously expressed by OPDP.”    The 2019 TV ad had also been reported to FDA under the FDA Bad Ad Program.

    It’s likely OPDP may have been moved to issue the Warning Letter because of the perception that the sponsor did not address FDA’s objections to the previous video in the new one.  Rather than making the safety information more thorough, the new video seems to omit even more risk information.  Another factor may have been the large viewing audience that may have seen the video, which was broadcast on television.  This may also make the corrective communication FDA requests in the Warning Letter more challenging.

    What is interesting and difficult to discern is whether CooperSurgical considered the video to be Paragard “promotion” and whether CooperSurgical had full control over the content of the video.  While the video is no longer available, OPDP describes the original broadcast on the lifestyle and entertainment show as promotional material that included the statement “sponsored by PARAGARD.”  Contrast this with OPDP’s 2019 Untitled Letter to Aclaris about a video interview that was broadcast on ABC’s The View, where OPDP cited the video as promotion and included reference to Aclaris’s Form 2253 submission, as well as the company’s re-posting of the video on the Eskata Facebook page and Aclaris LinkedIn page.  While industry may sponsor certain scientific and educational activities and not have those activities considered product promotion, there are guardrails, and DTC TV videos likely fall outside of them.   And, company intent about whether material is product “promotion” may ultimately be irrelevant to FDA’s determination.